ALLERGY, PROBIOTICS, AND INFANT FORMULAS

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ALLERGY, PROBIOTICS, AND INFANT FORMULAS

• Jon A. Vanderhoof MD
• Chief of Pediatric GI and Nutrition
• University of Nebraska Medical Center, Omaha Ne.
• Vice President, Global Medical Affairs
• Mead Johnson Nutritionals

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FOOD INTOLERANCE OR ALLERGY

• Formula protein intolerance
• Milk protein enteropathy
• Eosinophilic gastroenteritis
• Celiac disease

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FORMULA PROTEIN INTOLERANCE

• Incidence -- 2-7
• Proteins involved-milk, soy, hydrolysate, breast

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CLINICALPRESENTATION
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FORMULA PROTEIN ALLERGYTYPES

• Ige mediated-immediate -dramatic
• Non-ige mediated-less acute-more common

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GI SYMPTOMS

• Blood in stools
• Diarrhea
• Vomiting
• Irritability (colic)
• Failure to gain weight
• Nec

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FORMULA PROTEIN INTOLERANCESITE OF INJURY

• Small bowel-diarrhea-malabsorption-irritability
  -reflux
• Large bowel-blood in stools-loose, mucousy
  stools

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EXTRAINTESTINAL SYMPTOMS

• Cutaneous-atopic dermatitis
• Respiratory
• Central nervous system-irritability-sleep
  disturbances-colic

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IgE MEDIATED DISEASE

• Older children and adults
• Cutaneous, systemic manifestations
• Often foods other than milk
• Abrupt onset, resolution
• Normal biopsies

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FORMULA INTOLERANCENON-IgE CHARACTERISTICS

• Earlier onset
• Gi symptoms predominate
• Abnormal biopsies
• Insidious onset and resolution

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PROPOSED MECHANISMS

• Hyperpermeability of the newborn GI tract
• Immunological immaturity
• Immature gut barrier

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DIAGNOSIS
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RAST AND SKIN TESTCONSENSUS OPINION

• In IgE mediated disease, has excellent negative
  predictive value
• Positive test must be confirmed by double blind
  placebo controlled food challenge
• Tests are less helpful in non-ige mediated disease

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HISTOLOGYNON-IgE MEDIATED DISEASE

• gt60 eosinophils per 10 high power field in lamina
  propria
• Eos in crypt abscess
• Eos in muscularis mucosa
• Winter et al., Mod Pathol, 1990

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TREATMENT
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TREATMENT-INFANTSCHANGE FORMULA

• Soy
• Hydrolysate
• Amino acid
• Elimination diet for breast feeding mothers

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NEW SYNDROMES OF MILK ALLERGY

• Allergic esophagitis
• Allergic constipation
• Multiple formula protein intolerance

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CHRONIC CONSTIPATIONALLERGIC ORIGIN

• 27 Consecutive Infants Mean Age 20 Months With
  Constipation
• Cows Milk Protein Free Diet For 2 Month X 2
• Cows Milk Protein Challenges Following
  Resolution Of Symptoms In 21 Of 27
• No Improvement In 6
• Medical History Of Milk Intolerance In 15 Of 21
• Iacono Et Al., J Pediatr, 1995

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ALLERGIC CONSTIPATIONHISTOLOGY

• allergic proctitis(focal eosinophilia) 8 of 9
• small bowel biopsies 6 of 11
• abnormal-mild inflammation 5 of 6
  -eosinophilia 4 of 6
• gastric and esophageal biopsies -- all normal

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ALLERGIC CONSTIPATIONTYPICAL FEATURES

• History of milk intolerance as an infant
• Painful defecation
• Difficulty with defecation
• Poor response to chronic laxative therapy

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ALLERGIC ESOPHAGITIS

• Presentation - heartburn, dysphagia
• Histology - dense eosinophilic infiltrate
• Tip off - poor response to proton pump inhibitors
• Therapy - diet, steroids, cromolin

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DIETARY TREATMENT ALLERGIC ESOPHAGITIS

• Seven children mean age 11 years
• Dysphagia (3), pain(2), other(2)
• PPI-no improvement
• Strict milk free diet-total resolution

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OTHER TREATMENTS

• Oral fluticasone
• Oral montelukast
• Oral prednisone

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PROTEIN HYDROLYSATE INTOLERANCE

• Poor response to hydrolysate formulas-respond to
  amino acid formulas
• Similar presentation, histology to milk protein
  intolerance

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PROTEIN HYDROLYSATE INTOLERANCECLINICAL SYMPTOMS

• Irritability and crying in 14/16
• Vomiting in 9/16
• Diarrhea in 9/16
• Refusal to eat in 8/16
• Failure to thrive in 9/16
• de Boissieu et al.

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RESULTS

• Eosinophilic Proctitis
• 9 Infants-Age 75 Days (33-176 Days)-Treated
  With Chf 41 Days (14-173 Days)
• Focal Eosinophilia
• 10 Infants-Age 64 Days (37-124 Days)-Treated
  With Chf 36 Days (21-77 Days)
• Normal
• 1 Infants-Age 22 Days-Treated With Chf 22 Days

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FORMULA PROTEIN INTOLERANCEPROGNOSIS

• Resolution at varying times-most by 1 year-some
  earlier-some permanent
• Not all proteins resolved at same time

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PREVENTION

• Allergy is common in siblings
• No solid evidence to support or refute prenatal
  avoidance of antigens
• Some feeding options exist
• extensively hydrolyzed formulas
• partially hydrolyzed formulas
• breast-feeding
• probiotic supplemented formulas

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SPECIAL INFANT FORMULAS TO REDUCE ALLERGY RISK

• Extensively hydrolyzed formulas-superior to
  partial hydrolysates in high-risk infants
• Partial hydrolysates-may have some benefits
• Soy formulas-no evidence for protective effects

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ALLERGIC DISEASEENVIRONMENTAL FACTORS WHICH
AFFECT THE INCIDENCE

• Early daycare protective
• Allergy is more common in developed countries

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GASTROINTESTINAL ALLERGYROLE OF BACTERIA

• Th2 lymphocytes - humoral response -allergy
  mediated disease
• Th1 lymphocytes - cellular response -stimulated
  by bacteria -possibly influenced by
  probiotics

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PROBIOTICS COULD WE INFLUENCE THE RISK OF
ALLERGY?
Definition Live, human derived, organisms
which, when ingested, result in health benefits
including amelioration or prevention of a
specific disease state.
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COMMON PROBIOTIC ORGANISMS

• Lactobacillus
• Bifidobacteria
• Yeast

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PROBIOTICS IN ACUTE DIARRHEADEMONSTRATED BENEFITS

• Reduces duration, severity of viral diarrhea
• Reduces risk of travelers diarrhea
• Reduces incidence of diarrhea in daycare centers
• Reduces relapsing clostridium difficile diarrhea
• Reduces incidence of antibiotic-associated
  diarrhea

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BACKGROUNDPOTENTIAL MECHANISMS OF PROBIOTIC
EFFECTS

• Inhibition of adhesion
• Immunomodulation
• Production of antimicrobial substances
• Modification of toxins or toxin receptors
• Competition for nutrients
• Modification of other gut functions

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PROBIOTICS IN ACUTE DIARRHEADEMONSTRATED BENEFITS

• Reduces duration, severity of viral diarrhea
• Reduces risk of travelers diarrhea
• Reduces incidence of diarrhea in daycare centers
• Reduces relapsing clostridium difficile diarrhea
• Reduces incidence of antibiotic-associated
  diarrhea

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DIARRHEAL DAYS
4.00
3.20
2.40
Diarrhea Duration
1.60
0.80
0.00
Group 1
Group 2
Group 3
LGG-Powder
Placebo
LGG-Milk
p lt.001
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DURATION OF DIARRHEA
4.00
3.20
2.40
NUMBER OF DAYS
1.60
0.80
0.00
LGG
LACTOPHILUS
YALACTA
(n 14)
(n 19)
(n - 16)
Majamaa H, et al.
JPGN 199520333-38
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LGG IN ACUTE DIARRHEA
All
Rotavirus
Rotavirus -
n 287
n 101
n 186
130
104
78
Diarrhea Days
52
26
0
Placebo
LGG
p lt.05
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Duration of Diarrhea Expressed in the Form
of Kaplan-Meier Survival Estimates (pgt .1)
       
1.00
Placebo
0.75
Percent with Diarrhea
0.50
Treatment
0.25
0.00
0
50
100
150
Analysis time
         
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DIARRHEA EPISODES/MONTH
LGG AND PLACEBO
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17
N 119
13
LGG
10
Control
7
3
0
1 Month
2 Months
Distribution of diarrhea in treatment and placebo
groups in the daycare centers
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LACTOBACILLUS GG FOR TRAVELERSDIARRHEA IN
DEVELOPING COUNTRIES
PROTECTION RATE 47 (P 0.05)
10
8
6
Daily Risk
4
2
0
LGG
Placebo
Hilton et al, 1996
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MECHANISMS OF PROTECTION

• Competitive exclusion
• Alteration of intestinal mucin secretion
• Stimulation of immune response

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INTESTINAL ALLERGY

• Reduces translocation
• Tightens mucosal barrier

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EXTENT OF RASH IN INFANTS WITH MILK ALLERGY
PLACEBO
LACTOBACILLUS GG
15
10
12
8
9
6
SCORE A
SCORE A
6
4
3
2
0
0
Pre-treatment
Post-treatment
Pre-treatment
Post-treatment
LACTOBACILLUS GG
PLACEBO
15
15
12
12
9
9
SCORE C
SCORE C
6
6
3
3
0
0
Pre-treatment
Post-treatment
Pre-treatment
Post-treatment
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ALLERGY PREVENTIONLIVE VERSUS KILLED ORGANISMS

• Live or killed LGG added to extensively
  hydrolyzed formula and compared to control with
  no bacteria
• Heat inactivated LGG was associated with diarrhea
  and other GI symptoms
• Trend toward greater protection in live bacteria
  group
• Kirjavainen, et al JPGN Feb 2003

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CAN THIS INFORMATION BE TRANSLATED INTO A
THERAPEUTIC OPPORTUNITY?
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WHAT IS NEEDED?

• Extensively hydrolyzed formula
• Live bacteria
• Shelf stable product
• Bacterial strain with proven efficacy in allergy
  prevention

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STUDY OBJECTIVE

• Primary to compare 4 dose levels of lgg (0, 106,
  107, 108 cfus/gm dry weight)in healthy infants (
  0-3 months) during and at the end of an oral
  administration period.
• Secondary to examine clinical parameters of
  stool frequency, consistency, gas and fussiness
  an each dose level.

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FECAL COLONIZATION

• Participants were excluded if baseline stool
  samples were missing (3) or if LGG was present at
  baseline(2).
• 5 samples/paticipant were collected.
• LGG presence was defined as at least 1000 cfu/gm
  stool.
• Daily stool frequency consistency was recorded.

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RESULTSSTUDY POPULATION

• n 59, enrolled from oct 2001- march 2002.
• 4 were excluded due to incomplete collection of
  data or stools.
• Mean age 5 wks with avg wt of 4 kg.
• No difference in gender, sex or race was noted
  between groups.

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PRESENCE OF LGG IN STOOL SAMPLES

• LGG presence at end of test period
  (day21)3(23), 9(69), 11(85), 10(83) of
  infants in the 0, 106, 107, 108 cfu/gm groups
  respectively.
• LGG presence at follow-up (day 28)1(8), 8(62),
  5(45) 2(18) of infants in the 0, 106,107,108
  cfu/gm groups respectively.

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MEAN LOG10 COLONY COUNT FROM STUDY DAYS 0 - 28
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STOOL CHARACTERISTICSP gt 0.05
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TOLERANCE SYMPTOMSP gt O.O5
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SUMMARY

• Significant differences in colonization were
  noted during the test period between the control
  group all of the groups consuming different
  levels of LGG
• One week after LGG consumption ended, all groups
  continued to have quantifiable counts in their
  stools except the control group
• Two weeks after LGG consumption the 106 group
  continued to have significant levels in their
  stools compared to control

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CONCLUSIONS

• Allergic diseases of the GI tract are becoming
  more common and new syndromes are being
  recognized
• Certain strains of bacteria, especially LGG may
  have both a therapeutic and preventive role in
  these disorders
• Protein hydrolysate formulas containing LGG can
  be manufactured and do result in transient
  colonization of the gut